Early-Life Sodium Exposure Unmasks Susceptibility to Stroke in Hyperlipidemic, Hypertensive Heterozygous Tg25 Rats Transgenic for Human Cholesteryl Ester Transfer Protein
Background— Early-life risk factor exposure increases aortic atherosclerosis and blood pressure in humans and animal models; however, limited insight has been gained as to end-organ complications.
Methods and Results— We investigated the effects of early-life Na exposure (0.23% versus 0.4% NaCl regular rat chow) on vascular disease outcomes using the inbred, transgenic [hCETP]25 Dahl salt-sensitive hypertensive rat model of male-predominant coronary atherosclerosis, Tg25. Rather than the expected increase in coronary heart disease, fetal 0.4% Na exposure (≤2 g of Na per 2-kcal/d diet) induced adult-onset stroke in both sexes (ANOVA P<0.0001), with earlier stroke onset in Tg25 females. Analysis of later onset of 0.4% Na exposure resulted in decreased stroke risk and later stroke onset despite longer 0.4% Na exposure durations, which indicates increasing risk with earlier onset of 0.4% Na exposure. Histological analysis of stroke-positive rat brains revealed cerebral cortical hemorrhagic infarctions, microhemorrhages, neuronal ischemia, and microvascular injury. Ex vivo MRI of stroke-positive rat brains detected cerebral hemorrhages, microhemorrhages, and ischemia with middle cerebral artery distribution and cerebellar noninvolvement. Ultrasound microimaging detected carotid artery disease. Prestroke analysis detected neuronal ischemia and decreased mass of isolated cerebral but not cerebellar microvessels.
Conclusions— Early-life Na exposure exacerbated hypertension and unmasked stroke susceptibility, with greater female vulnerability in hypertensive, hyperlipidemic Tg25 rats. The reproducible modeling in stroke-prone Tg25 rats of carotid artery disease, cerebral hemorrhagic infarctions, neuronal ischemia, microhemorrhages, and microvascular alterations suggests a pathogenic spectrum with causal interrelationships. This “mixed-stroke” spectrum could represent paradigms of ischemic-hemorrhagic transformation and/or a microangiopathic basis for the association of ischemic lesions, microhemorrhages, and strokes in humans. Together, the data reveal early-life Na exposure to be a significant modifier of hypertension and stroke disease course and hence a potentially modifiable prevention target that deserves systematic study.
Received November 4, 2008; accepted January 7, 2009.